Dynamic conformational changes of extracellular S5-P linkers in the hERG channel
Dynamic conformational changes of extracellular S5-P linkers in the hERG channel
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DOI：
10.1113/jphysiol.2005.093682
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发表时间：
2005-11-15
影响因子：
5.5
通讯作者：
Tseng, GN
中科院分区：
文献类型：
--
作者：
Jiang, M;Zhang, M;Tseng, GN
hERG 通道有一个异常长的“S5-P 连接子”（残基 571-613），排列在孔的外口。之前，我们已经证明，S5-P 连接子上的残基对于 hERG 通道的快速失活过程和 K+ 选择性至关重要。在这里，我们使用了多种方法来探测该 S5-P 连接子的结构及其与 hERG 通道其他结构域的相互作用。合成 hERG S5-P 连接肽的圆二色性和 NMR 分析表明，该连接肽非常动态：其中心区域（位置 583-593）可以是非结构化的或螺旋的，具体取决于它是否浸入水相中或与疏水环境接触。引入S5-P接头的583-597位的半胱氨酸可以形成亚基间二硫键，并且其中至少四个（584、585、588和589）可以与相邻亚基的对应物形成二硫键。我们提出 hERG 通道中的四个 S5-P 连接子可以在通道门控过程中参与动态构象变化，并且来自相邻亚基的 S5-P 连接子之间的相互作用对通道失活有重要贡献。
The hERG channel has an unusually long 'S5-P linker' (residues 571-613) that lines the outer mouth of the pore. Previously, we have shown that residues along this S5-P linker are critical for the fast-inactivation process and K+ selectivity of the hERG channel. Here we used several approaches to probe the structure of this S5-P linker and its interactions with other domains of the hERG channel. Circular dichroism and NMR analysis of a synthetic hERG S5-P linker peptide suggested that this linker is quite dynamic: its central region (positions 583-593) can be unstructured or helical, depending on whether it is immersed in an aqueous phase or in contact with a hydrophobic environment. Cysteine introduced into positions 583-597 of the S5-P linker can form intersubunit disulphide bonds, and at least four of them (at 584, 585, 588 and 589) can form disulphide bonds with counterparts from neighbouring subunits. We propose that the four S5-P linkers in a hERG channel can engage in dynamic conformational changes during channel gating, and interactions between S5-P linkers from neighbouring subunits contribute importantly to channel inactivation.